PROJECT SUMMARY In 2006 Yale started the innovative Medical Research Scholars Program (MRSP) with the mission of providing broad and deep Ph.D. training in the core basic science concepts of molecular biology, cell biology, biochemistry, genetics, physiology, pharmacology, and pathology, integrated with intensive exposure to medically oriented coursework and mentored clinical experiences designed specifically for Ph.D. students. The ultimate goal of this training is to prepare our students to be future interdisciplinary leaders in the biomedical sciences, with a unique ability to pursue clinically relevant fundamental basic science inquiry aimed at elucidating the molecular mechanisms of disease. Until the award of the first five years of NIGMS T32 support that we are now seeking to renew, MRSP had been supported by a combination of institutional funds and funds provided by the Howard Hughes Medical Institute (HHMI). Termination of HHMI support after the 2013-2014 academic year, and the desire to continue this highly successful ongoing program constituted the rationale for applying for the first five-year award of this Molecular Medicine (MM) Training Grant, which supported four trainee slots per year. Yale University supports all first-year PhD students in the biomedical sciences, and thus this T32 supports two second-year and two thrid-year students each year. MRSP students participate in a variety of program activities designed to engage Ph.D. students in medically relevant training and experiences throughout their graduate studies. The classes focus first on normal human physiology, organ-based cell biology, and biostatistics, followed by human pathobiology and an introduction to drug discovery, validation, and clinical trials. MRSP students also have the option to participate with first-year Yale MD students in weekly small-group physiology ?case conference? tutorials, in which they explore in depth the physiological underpinnings of particular disease states. The cornerstone of the MRSP is a two-year mentored clinical experience that provides students with in-depth exposure to the science behind human diseases and first-hand longitudinal encounters with patients to contextualize the mechanistic basis of disease in a way that is not possible through traditional classroom learning. In addition to these formal activities, the MRSP also provides ongoing mentoring to all MRSP trainees regarding selection of a thesis research laboratory and assembly of the dissertation committee to support the goal of the NIGMS Molecular Medicine program to provide training in the basic biomedical sciences with a focus on elucidating the mechanisms of human disease. Based on the great demand for admission into the MRSP by outstanding training-grant-eligible students already admitted to Yale's umbrella biomedical sciences PhD program, we are requesting an increase in the number of annual slots from four to six, which would allow us to support three second-year and three third-year students each year.